EP0230402B1 - Dérivés d'alkylol pharmacologiquement actifs - Google Patents
Dérivés d'alkylol pharmacologiquement actifs Download PDFInfo
- Publication number
- EP0230402B1 EP0230402B1 EP87830012A EP87830012A EP0230402B1 EP 0230402 B1 EP0230402 B1 EP 0230402B1 EP 87830012 A EP87830012 A EP 87830012A EP 87830012 A EP87830012 A EP 87830012A EP 0230402 B1 EP0230402 B1 EP 0230402B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- piperazin
- dihydroxypropyl
- hydroxy
- alkylol
- propane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- -1 hydroxy, methylthio Chemical group 0.000 claims abstract description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims abstract description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 6
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 5
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 150000001408 amides Chemical class 0.000 claims abstract description 4
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims abstract description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims abstract description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000005907 alkyl ester group Chemical group 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229930192474 thiophene Natural products 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 4
- 239000004146 Propane-1,2-diol Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 229960004063 propylene glycol Drugs 0.000 claims description 2
- 235000013772 propylene glycol Nutrition 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims 6
- 235000001968 nicotinic acid Nutrition 0.000 claims 3
- 239000011664 nicotinic acid Substances 0.000 claims 3
- 229960003512 nicotinic acid Drugs 0.000 claims 3
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims 2
- 239000003085 diluting agent Substances 0.000 claims 1
- 235000005152 nicotinamide Nutrition 0.000 claims 1
- 239000011570 nicotinamide Substances 0.000 claims 1
- 229960003966 nicotinamide Drugs 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 230000000954 anitussive effect Effects 0.000 abstract description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 abstract 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 abstract 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- UXQHRRWIFFJGMQ-UHFFFAOYSA-N 3-piperazin-1-ylpropane-1,2-diol Chemical compound OCC(O)CN1CCNCC1 UXQHRRWIFFJGMQ-UHFFFAOYSA-N 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Substances OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 230000008018 melting Effects 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 6
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IBRSSZOHCGUTHI-UHFFFAOYSA-N 2-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Cl IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 230000000284 resting effect Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 229940125717 barbiturate Drugs 0.000 description 3
- 229960004126 codeine Drugs 0.000 description 3
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- KXRMAMCTANFMNJ-UHFFFAOYSA-N 2-[4-(2,3-dihydroxypropyl)-1,4-diazepan-1-yl]pyridine-3-carboxylic acid Chemical compound C1CN(CC(O)CO)CCCN1C1=NC=CC=C1C(O)=O KXRMAMCTANFMNJ-UHFFFAOYSA-N 0.000 description 2
- ZPRVUZVREIMZIV-UHFFFAOYSA-N 2-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=C1N1CCN(CC(O)CO)CC1 ZPRVUZVREIMZIV-UHFFFAOYSA-N 0.000 description 2
- QJKLWOJYVXEBBA-UHFFFAOYSA-N 2-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyridine-3-carboxylic acid Chemical compound C1CN(CC(O)CO)CCN1C1=NC=CC=C1C(O)=O QJKLWOJYVXEBBA-UHFFFAOYSA-N 0.000 description 2
- HOSQTKZRBVNNBB-UHFFFAOYSA-N 2-[4-(2-hydroxypropyl)piperazin-1-yl]pyridine-3-carboxylic acid Chemical compound C1CN(CC(O)C)CCN1C1=NC=CC=C1C(O)=O HOSQTKZRBVNNBB-UHFFFAOYSA-N 0.000 description 2
- IAORHHNTYRMLCP-UHFFFAOYSA-N 2-[4-(3-hydroxypropyl)piperazin-1-yl]pyridine-3-carboxylic acid Chemical compound C1CN(CCCO)CCN1C1=NC=CC=C1C(O)=O IAORHHNTYRMLCP-UHFFFAOYSA-N 0.000 description 2
- PTVWPYVOOKLBCG-UHFFFAOYSA-N 3-(4-phenyl-1-piperazinyl)propane-1,2-diol Chemical compound C1CN(CC(O)CO)CCN1C1=CC=CC=C1 PTVWPYVOOKLBCG-UHFFFAOYSA-N 0.000 description 2
- BXHWCXPBIIQWJV-UHFFFAOYSA-N 3-(4-pyridin-2-ylpiperazin-1-yl)propane-1,2-diol;dihydrochloride Chemical compound Cl.Cl.C1CN(CC(O)CO)CCN1C1=CC=CC=N1 BXHWCXPBIIQWJV-UHFFFAOYSA-N 0.000 description 2
- CZSHIUXMFNOFGH-UHFFFAOYSA-N 3-(4-pyrimidin-2-ylpiperazin-1-yl)propane-1,2-diol Chemical compound C1CN(CC(O)CO)CCN1C1=NC=CC=N1 CZSHIUXMFNOFGH-UHFFFAOYSA-N 0.000 description 2
- OGPORMMRKXDINX-UHFFFAOYSA-N 3-[4-(1,3-thiazol-2-yl)piperazin-1-yl]propane-1,2-diol Chemical compound C1CN(CC(O)CO)CCN1C1=NC=CS1 OGPORMMRKXDINX-UHFFFAOYSA-N 0.000 description 2
- XCRNNQDKZSGYMS-UHFFFAOYSA-N 3-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyridazine-4-carbonitrile;dihydrochloride Chemical compound Cl.Cl.C1CN(CC(O)CO)CCN1C1=NN=CC=C1C#N XCRNNQDKZSGYMS-UHFFFAOYSA-N 0.000 description 2
- LTNGFOVAOOXWDM-UHFFFAOYSA-N 3-[4-(3-hydroxypyridin-2-yl)piperazin-1-yl]propane-1,2-diol;dihydrochloride Chemical compound Cl.Cl.C1CN(CC(O)CO)CCN1C1=NC=CC=C1O LTNGFOVAOOXWDM-UHFFFAOYSA-N 0.000 description 2
- RDAFBNWKCUBBHI-UHFFFAOYSA-N 6-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyridine-3-carboxylic acid Chemical compound C1CN(CC(O)CO)CCN1C1=CC=C(C(O)=O)C=N1 RDAFBNWKCUBBHI-UHFFFAOYSA-N 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- PTJGLFIIZFVFJV-UHFFFAOYSA-N N'-hydroxy-N-(3-pyridinyl)octanediamide Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CN=C1 PTJGLFIIZFVFJV-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000010513 Stupor Diseases 0.000 description 2
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 2
- 229960004722 dropropizine Drugs 0.000 description 2
- IJECEMMDGYTXND-UHFFFAOYSA-N ethyl 3-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyridazine-4-carboxylate Chemical compound CCOC(=O)C1=CC=NN=C1N1CCN(CC(O)CO)CC1 IJECEMMDGYTXND-UHFFFAOYSA-N 0.000 description 2
- RPWCLVDKRZHCRK-UHFFFAOYSA-N ethyl 4-[4-(2,3-dihydroxypropyl)piperazin-1-yl]-2-methylsulfanylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)N=C1N1CCN(CC(O)CO)CC1 RPWCLVDKRZHCRK-UHFFFAOYSA-N 0.000 description 2
- RPIDRPNODSLJMZ-UHFFFAOYSA-N ethyl 4-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyrimidine-5-carboxylate;dihydrochloride Chemical compound Cl.Cl.CCOC(=O)C1=CN=CN=C1N1CCN(CC(O)CO)CC1 RPIDRPNODSLJMZ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- YCDXZRCKXFROCW-UHFFFAOYSA-N methyl 3-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyrazine-2-carboxylate;dihydrochloride Chemical compound Cl.Cl.COC(=O)C1=NC=CN=C1N1CCN(CC(O)CO)CC1 YCDXZRCKXFROCW-UHFFFAOYSA-N 0.000 description 2
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- 230000011514 reflex Effects 0.000 description 2
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- KDAAPRDOGPQQJE-UHFFFAOYSA-M sodium;3-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyrazine-2-carboxylate Chemical compound [Na+].C1CN(CC(O)CO)CCN1C1=NC=CN=C1C([O-])=O KDAAPRDOGPQQJE-UHFFFAOYSA-M 0.000 description 2
- ZWBQFIKOTMQHDN-UHFFFAOYSA-M sodium;4-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyrimidine-5-carboxylate Chemical compound [Na+].C1CN(CC(O)CO)CCN1C1=NC=NC=C1C([O-])=O ZWBQFIKOTMQHDN-UHFFFAOYSA-M 0.000 description 2
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 1
- XAKIZRLIXGLPBW-UHFFFAOYSA-N 1-piperazin-1-ylpropan-2-ol Chemical compound CC(O)CN1CCNCC1 XAKIZRLIXGLPBW-UHFFFAOYSA-N 0.000 description 1
- RXNZFHIEDZEUQM-UHFFFAOYSA-N 2-bromo-1,3-thiazole Chemical compound BrC1=NC=CS1 RXNZFHIEDZEUQM-UHFFFAOYSA-N 0.000 description 1
- YKHQFTANTNMYPP-UHFFFAOYSA-N 2-bromopyridin-3-ol Chemical compound OC1=CC=CN=C1Br YKHQFTANTNMYPP-UHFFFAOYSA-N 0.000 description 1
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- ZQZAHPFFZWEUCL-UHFFFAOYSA-N 2-chloropyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=C1Cl ZQZAHPFFZWEUCL-UHFFFAOYSA-N 0.000 description 1
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 1
- WQFWIVTXNKRNJZ-UHFFFAOYSA-N 2-piperazin-1-yl-1,3-thiazole Chemical class C1CNCCN1C1=NC=CS1 WQFWIVTXNKRNJZ-UHFFFAOYSA-N 0.000 description 1
- GUSWJGOYDXFJSI-UHFFFAOYSA-N 3,6-dichloropyridazine Chemical compound ClC1=CC=C(Cl)N=N1 GUSWJGOYDXFJSI-UHFFFAOYSA-N 0.000 description 1
- VTKCJTJAHZUSEU-UHFFFAOYSA-N 3-(1,4-diazepan-1-yl)propane-1,2-diol Chemical compound OCC(O)CN1CCCNCC1 VTKCJTJAHZUSEU-UHFFFAOYSA-N 0.000 description 1
- PGDZOSDCBDJOKQ-UHFFFAOYSA-N 3-(4-pyrazin-2-ylpiperazin-1-yl)propane-1,2-diol Chemical compound C1CN(CC(O)CO)CCN1C1=CN=CC=N1 PGDZOSDCBDJOKQ-UHFFFAOYSA-N 0.000 description 1
- MIFRLIVIAJDDPZ-UHFFFAOYSA-N 3-(4-thiophen-2-ylpiperazin-1-yl)propane-1,2-diol Chemical compound C1CN(CC(O)CO)CCN1C1=CC=CS1 MIFRLIVIAJDDPZ-UHFFFAOYSA-N 0.000 description 1
- PJJUFILTKQBKQG-UHFFFAOYSA-N 3-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyrazine-2-carboxylic acid Chemical compound C1CN(CC(O)CO)CCN1C1=NC=CN=C1C(O)=O PJJUFILTKQBKQG-UHFFFAOYSA-N 0.000 description 1
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- CQNWPJDJRNENDL-UHFFFAOYSA-N 3-[4-(6-methoxypyridazin-3-yl)piperazin-1-yl]propane-1,2-diol Chemical compound N1=NC(OC)=CC=C1N1CCN(CC(O)CO)CC1 CQNWPJDJRNENDL-UHFFFAOYSA-N 0.000 description 1
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- 125000004432 carbon atom Chemical group C* 0.000 description 1
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- UAEJFCPXIREEHM-UHFFFAOYSA-N ethyl 3-chloropyridazine-4-carboxylate Chemical compound CCOC(=O)C1=CC=NN=C1Cl UAEJFCPXIREEHM-UHFFFAOYSA-N 0.000 description 1
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- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- WFUIZCOPYSLJAG-UHFFFAOYSA-N methyl 2-[4-(2,3-dihydroxypropyl)piperazin-1-yl]thiophene-3-carboxylate Chemical compound C1=CSC(N2CCN(CC(O)CO)CC2)=C1C(=O)OC WFUIZCOPYSLJAG-UHFFFAOYSA-N 0.000 description 1
- MWFUBVWIRWTOFC-UHFFFAOYSA-N methyl 3-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyrazine-2-carboxylate Chemical compound COC(=O)C1=NC=CN=C1N1CCN(CC(O)CO)CC1 MWFUBVWIRWTOFC-UHFFFAOYSA-N 0.000 description 1
- SSXOFWYPCZOGBM-UHFFFAOYSA-N methyl 3-chloropyrazine-2-carboxylate Chemical compound COC(=O)C1=NC=CN=C1Cl SSXOFWYPCZOGBM-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical class C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000294 tussive effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/20—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
Definitions
- the subject of the present invention relates to a new class of alkylol derivatives which show an interesting activity as antitussive agents.
- the compounds of the invention are represented by alkylolpiperazine and alkylolhomopiperazine derivatives belonging to the general formula where R represents a 5 or 6 membered heterocylic ring selected among pyridine, pyrimidine, pyrazine, pyridazine, thiophene and furan which may be substituted with one or more groups selected among alkyl, trifluoromethyl, methylthio, alkoxy, halogen, amide, hydroxy, cyano, carboxy and the alkyl esters and the salts with alkali metals thereof or R represents an unsubstituted thiazolyl group n is an integer such as 2 or 3 X and X' represent each a hydrogen atom or hydroxy group with the exception of both being hydrogen atom, and X' may be also a substituted hydroxy group and the corresponding non toxic pharmaceutically acceptable acid addition salts, except the compound 3-[4-(2'-pyridyl)-piperazin-1-
- the compounds of formula I display a marked antitussive activity and, at their active dose, practically they are free of the undesired side effects which generally are shown by the compounds on the market having analogous activity.
- the process for preparing the compounds of formula I is essentially based on reacting a heterocyclic derivative R-Hal (II), where R has the above-cited meaning and Hal represents a halogen atom, preferably a chlorine atom, with a piperazine or homopiperazine alkylol derivative (III), in a suitable organic solvent at a temperature generally comprised between 60 and 130°C.
- R-Hal a heterocyclic derivative
- Hal represents a halogen atom, preferably a chlorine atom
- a piperazine or homopiperazine alkylol derivative (III) in a suitable organic solvent at a temperature generally comprised between 60 and 130°C.
- the reaction can be schematically represented as following where the symbols R, Hal, n, X and X' have the above mentioned meaning.
- the compounds I are isolated according to the known technique, in good yield and purity state.
- alkyl or alkoxy is used through the description to mean an alkyl or alkoxy radical having from 1 to 3 carbon atoms respectively.
- substituted hydroxy means a hydroxy group substituted with an alkyl or with a hydroxyalkyl.
- R represents an optionally substituted pyridin-2-yl radical
- n is 2
- X and X' are both hydroxy group.
- the compounds I when the carboxy group is present and when desired, may be converted in a manner known per se into the corresponding alkali metal salts and they may be isolated as non-toxic addition salts with suitable acids.
- the compounds according to the present invention are used in the form of pharmaceutical preparation which contain said compounds in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient suitable for oral or parenteral administration.
- pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient suitable for oral or parenteral administration.
- the compounds of the invention may be contained in these pharmaceu tical preparation in the form of free base or in the form of their non-toxic acid addition salts.
- the inorganic acids which may be employed to prepare these acid addition salts may be, for example, hydrochloric, hydrobromic, or sulphuric acid.
- the organic acids which may be employed are, for example, maleic, citric, fumaric and succinic acid.
- the pharmaceutical preparations may be in solid form as capsules, tablets, dragees or suppositories, or in liquid form such as solutions, suspensions or emulsions. If desired, there may be included in the above preparations auxiliary substances such as stabilizing agents and other commonly used additives, or there may be contained other therapeutically active agents suitable to be administered together with the componds of the invention. While the dosage of the compounds will vary from the administration route and will also depend upon the age and condition of the patient, a dosage unit from about 1 to about 20 mg per kilogram of body weight per day, can be orally administered.
- the antitussive activity of the compounds of the invention has been evaluated using as comparison compounds both dropropizine, which represents the antitissive compound having the closest chemical structure analogy with the compounds of the invention, and codeine.
- the compounds of the invention compared to the standard at the same dose, showed to be endowed with a higher or comparable activity and to be practically devoided of undesired side effects.
- tests for determining the effect on the sleeping time interval induced by barbiturate administration were carried out. Tests were performed on the compounds of formula I according to the methods herebelow reported and gave the results listed in Tables 1 and 2.
- the animals were selected the day before and allowed to the test only if they showed a number of short coughs equal or higher than 10.
- Table 1 Compound Dose mg/Kg p.o. Inhibition % p* Codeine 100 63.17 ⁇ 0.001 Dropropizine( ⁇ ) 100 48.57 ⁇ 0.01
- Example 1 100 42.80 ⁇ 0.01
- Example 2 100 29.95 ⁇ 0.02
- Example 3 100 51.66 ⁇ 0.01
- Example 4 100 29.80 ⁇ 0.02
- Example 5 100 64.01 ⁇ 0.001
- Example 6 100 45.15 ⁇ 0.01
- Example 7 100 60.00 ⁇ 0.001 * "t" of Student for paired data.
- the sleep was induced by intraperitoneal administration of 40 mg/Kg pentobarbital sodium.
- the narcosis start was considered from the moment when the animal, lying on its back, lost its straightening reflex.
- the narcosis end was considered from the moment when the animal recovered such reflex. (Turner R. in "Screening Methods in Pharmacology", Academic Press, 6 ,70,1985).
- the compounds under examination were orally administered 1 hour before the barbiturate administration; to the control animals 10 ml/Kg tap water were administered.
- Table 2 Compound Dose mg/Kg p.o. ⁇ % p* Codeine 100 + 122.56 ⁇ 0.001 Dropropisine ( ⁇ ) 100 + 153.80 ⁇ 0.001
- Example 1 100 + 35.12 ⁇ 0.05
- Example 2 100 + 3.03 NS
- Example 3 100 + 13.42
- Example 4 100 - 3.58 NS
- Example 5 100 - 10.23 NS
- Example 6 100 + 1.22 NS
- Example 7 100 - 12.80 NS * "t" of Student NS not significant
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Compounds Of Unknown Constitution (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pyridine Compounds (AREA)
Claims (11)
- Dérivés à groupement alkylol, ayant la formule structurale
- Dérivés à groupement alkylol selon la revendication 1, caractérisés en ce que n est 2.
- Dérivés à groupement alkylol selon la revendication 1, caractérisés en ce que n est 3.
- Dérivés à groupement alkylol selon la revendication 1, caractérisés en ce que R est un radical pyridine-2-yle facultativement substitué, n est 2, et X et X' sont chacun un groupe hydroxyle.
- Acide 2-[4-(2,3-dihydroxypropyl)pipérazine-1-yl]nicotinique.
- 3-[4-(6-chloropyridazine-3-yl)pipérazine-1-yl]-propane-1,2-diol.
- 2-[4-(2,3-dihydroxypropyl)pipérazine-1-yl]-nicotinamide.
- Acide 6-[4-(2,3-dihydroxypropyl)pipérazine-1-yl]nicotinique.
- Acide 2-[4-(2,3-dihydroxypropyl)homopipérazine-1-yl]nicotinique.
- Procédé par analogie pour la préparation de dérivés à groupement alkylol selon la revendication 1, caractérisé en ce qu'un dérivé hétérocyclique R-Hal, où R est tel que défini précédemment et Hal représente un atome d'halogène, est amené à réagir dans un solvant organique approprié à une température comprise entre 60 et 130°C avec un dérivé à groupement alkylol de formule
- Composition pharmaceutique contenant une quantité active d'un ou plusieurs composés selon les revendications 1 à 9 en mélange avec un ou plusieurs diluants pharmaceutiquement acceptables.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT87830012T ATE88467T1 (de) | 1986-01-20 | 1987-01-16 | Pharmakologisch aktive alkylol-derivate. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT1912186 | 1986-01-20 | ||
IT19121/86A IT1191845B (it) | 1986-01-20 | 1986-01-20 | Alchiloli derivati farmacologicamente attivi |
Publications (3)
Publication Number | Publication Date |
---|---|
EP0230402A2 EP0230402A2 (fr) | 1987-07-29 |
EP0230402A3 EP0230402A3 (en) | 1989-02-22 |
EP0230402B1 true EP0230402B1 (fr) | 1993-04-21 |
Family
ID=11154912
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP87830012A Expired - Lifetime EP0230402B1 (fr) | 1986-01-20 | 1987-01-16 | Dérivés d'alkylol pharmacologiquement actifs |
Country Status (7)
Country | Link |
---|---|
US (1) | US4849422A (fr) |
EP (1) | EP0230402B1 (fr) |
JP (1) | JPS62169768A (fr) |
AT (1) | ATE88467T1 (fr) |
DE (1) | DE3785463T2 (fr) |
ES (1) | ES2056836T3 (fr) |
IT (1) | IT1191845B (fr) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2664238B2 (ja) * | 1989-03-01 | 1997-10-15 | 日清製粉株式会社 | ニコチン酸またはそのエステル誘導体 |
FR2675799B1 (fr) * | 1991-04-24 | 1993-12-24 | Synthelabo | Derives de 2-aminopyrimidine-4-carboxamide, leur preparation et leur application en therapeutique. |
WO2004083235A2 (fr) * | 2003-03-19 | 2004-09-30 | Exelixis Inc. | Modulateurs de tie-2 et procedes d'utilisation |
WO2005118543A1 (fr) * | 2004-06-03 | 2005-12-15 | Ono Pharmaceutical Co., Ltd. | Inhibiteur des kinases et utilisation de cet inhibiteur |
ES2435790T3 (es) | 2004-12-03 | 2013-12-23 | Intervet International B.V. | Piperazinas sustituidas como antagonistas de CB1 |
CA2637565A1 (fr) | 2006-01-18 | 2007-07-26 | Schering Corporation | Modulateurs de recepteurs de cannibinoides |
WO2009005645A1 (fr) * | 2007-06-28 | 2009-01-08 | Schering Corporation | Pipérazines substituées en tant qu'antagonistes de cb1 |
BRPI0814806A2 (pt) | 2007-06-28 | 2015-02-03 | Intervet Int Bv | Pirazinas substituídas como antagonistas de cb1 |
JP6047830B2 (ja) * | 2013-03-12 | 2016-12-21 | 花王株式会社 | ホモピペラジン誘導体を含む漂白剤組成物 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4064244A (en) * | 1973-02-02 | 1977-12-20 | Sandoz Ltd. | Organic compounds |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2257294B1 (fr) * | 1973-07-06 | 1977-07-01 | Ugine Kuhlmann | |
HU173380B (hu) * | 1977-02-25 | 1979-04-28 | Richter Gedeon Vegyeszet | Sposob poluchenija novogo proizvodnogo piridil-piperazina i kislo-additivnykh solejj |
EP0094159B1 (fr) * | 1982-05-10 | 1990-03-14 | Takeda Chemical Industries, Ltd. | Dérivés de la dihydropyridine, leur préparation et leur application |
DE3443698A1 (de) * | 1984-11-30 | 1986-06-05 | Sandoz-Patent-GmbH, 7850 Lörrach | Neue piperazinderivate, verfahren zu ihrer herstellung und ihre verwendung |
-
1986
- 1986-01-20 IT IT19121/86A patent/IT1191845B/it active
-
1987
- 1987-01-16 ES ES87830012T patent/ES2056836T3/es not_active Expired - Lifetime
- 1987-01-16 EP EP87830012A patent/EP0230402B1/fr not_active Expired - Lifetime
- 1987-01-16 US US07/004,028 patent/US4849422A/en not_active Expired - Fee Related
- 1987-01-16 AT AT87830012T patent/ATE88467T1/de not_active IP Right Cessation
- 1987-01-16 DE DE87830012T patent/DE3785463T2/de not_active Expired - Fee Related
- 1987-01-19 JP JP62008371A patent/JPS62169768A/ja active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4064244A (en) * | 1973-02-02 | 1977-12-20 | Sandoz Ltd. | Organic compounds |
Also Published As
Publication number | Publication date |
---|---|
EP0230402A3 (en) | 1989-02-22 |
IT1191845B (it) | 1988-03-23 |
ATE88467T1 (de) | 1993-05-15 |
DE3785463D1 (de) | 1993-05-27 |
US4849422A (en) | 1989-07-18 |
DE3785463T2 (de) | 1993-11-18 |
EP0230402A2 (fr) | 1987-07-29 |
ES2056836T3 (es) | 1994-10-16 |
IT8619121A0 (it) | 1986-01-20 |
JPS62169768A (ja) | 1987-07-25 |
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